Asthma and atopic dermatitis are the two major allergic diseases, which are caused by chronic inflammation affecting lung airways and skin, respectively. In addition to the clinical and pathological similarities between asthma and atopic dermatitis, both complications develop frequently in the same patient, suggesting a common etiology particularly during childhood. Importantly, the recent molecular studies have identified thymic stromal lymphopoietin (TSLP) as a common initiating factor causing both disorders. TSLP is an epithelial-derived IL-7-like cytokine capable of activating dendritic cell-mediated T helper 2 inflammation, which is central in pathogenesis of asthma and atopic dermatitis. Although the molecular pathways connecting TSLP to the inflammation and disease have been studied extensively, the mechanism stimulating lung and skin epithelial cells to overexpress TSLP is not fully understood. The current dogma favors the role that allergens/pathogens may play in causing epithelial TSLP overexpression. It argues that defective epithelial-barrier function allows the invading agents to directly contact and injure the epithelial cells, inducing them to release TSLP as a secondary effect. Our recent findings, however, demonstrated that aberrant barrier formation itself serves as a potent stimulus inducing TSLP overexpression by epithelial cells. Therefore, it is intriguing to hypothesize that intrinsic epithelial differentiation/barrier formation defects that precede the need for a functional barrier, are the primary cause of TSLP overexpression by the epithelia that fail to properly differentiate. To test this hypothesis, this project will focus on a model organ that is extensively studied in our lab, the mouse skin. The proposed specific aims will examine (I) how epidermal differentiation/barrier formation defects (intrinsic factors) cause TSLP overexpression at the molecular level and (II) if barrier dysfunction (extrinsic factor(s)) is able to induce TSLP overexpression by the skin that has a transient or chronic barrier defect. Achievement of these aims will extend our recent discovery, establishing the role of environment and genetics in regulating epithelial TSLP overproduction, also identifying the signaling pathway mediating the cell autonomous aspect of such an effect. Ultimately, it will determine the relative importance of intrinsic epithelial defects in the development of asthma and atopic dermatitis, opening up a novel therapeutic approach to treat these chronic diseases. More than 20 million Americans suffer from asthma, which together with atopic dermatitis account for the majority of chronic allergic diseases affecting children and adults. Thus, better treatment for these conditions will benefit a large group of patients and significantly reduce the burden on the healthcare system.